Diagnosis Of Familial Hypercholesterolemia Research Articles

A Data-Driven Comparative Analysis of Machine-Learning Models for Familial Hypercholesterolemia Detection

This study presents an assessment of familial hypercholesterolemia (FH) probability using different algorithms (CatBoost, XGBoost, Random Forest, SVM) and its ensembles, leveraging electronic health record data. The primary objective is to explore an enhanced method for estimating FH probability, surpassing the currently recommended Dutch Lipid Clinic Network (DLCN) Score. The models were trained using the largest Polish cohort of patients enrolled in an FH clinic, all of whom underwent genetic testing for FH-associated mutations. The initial dataset comprised over 100 parameters per patient, which was reduced to 48 clinically accessible features to ensure applicability in routine outpatient settings. To preserve balance, the data were stratified according to DLCN score ranges (<0–2>, <3–5>, <6–8>, and ≥9), representing varying levels of FH likelihood. The dataset was then split into training and test sets with an 80/20 ratio. Machine-learning models were trained, with hyperparameters optimized via grid search. The accuracy of the DLCN score in predicting FH was first evaluated by examining the proportion of patients with positive DNA tests relative to those with a DLCN score of 6 and above, the threshold for genetic testing. The DLCN score demonstrated an accuracy of approximately 40%. In contrast, the CatBoost model and its ensembles achieved over 80% accuracy. While the DLCN score remains a clinically valuable tool, its diagnostic accuracy is limited. The findings indicate that the ML models offer a substantial improvement in the precision of FH diagnosis, demonstrating its potential to enhance clinical decision making in identifying patients with FH.

Phenotypic and genotypic features of children with familial hypercholesterolemia

Dyslipidemia is a metabolic disorder in which the ratio of lipid particles in the blood changes. It is often associated with other conditions and diseases during childhood. Lipid metabolism disorders in children can be divided into two categories: primary, which are inherited from parents or occur de novo, and secondary, which occur during life. Familial hypercholesterolemia is the most common type of primary disorder, characterized by an increase in blood lipoprotein levels. However, the lipid composition in children with established familial hypercholesterolemia can vary. One factor that may contribute to higher lipid levels in these children is the presence of mutations in the apolipoprotein E gene.Purpose of the study was to investigate the phenotypic and genotypic features of children with familial hypercholesterolemia in order to better understand this condition.Materials and methods. Children with a clinical diagnosis of familial hypercholesterolemia underwent DNA sequencing to identify mutations in genes related to LDLR, APOB, LDLRAP1, and APOE genes.Results. Children with familial hypercholesterolemia most often carry the polymorphism c.388T>C in the ApoE gene (g.45411941T>C, p.Cys130Arg, rs429358). Also, 24.1% of children were found to be isolated carriers of various ApoE haplotypes, which are risk factors for dyslipidemia. In children with a pathogenic mutation characteristic of familial hypercholesterolemia and carriage of polymorphisms in the ApoE gene, the LDL level was statistically higher compared to non-carriers.Conclusion. Carriage of various polymorphisms in the ApoE gene in children with familial hypercholesterolemia may lead to an increase in the already elevated levels of LDL and total cholesterol.

Abstract 4113942: Validation of Changes in the Cutoff Values of Achilles Tendon Thickness on Radiography in the Clinical Criteria of Heterozygous Familial Hypercholesterolemia in Japan

Background: To increase sensitivity and maintain specificity, the 2022 Japan Atherosclerosis Society familial hypercholesterolemia (FH) clinical criteria was modified. In particular, the cutoff value of Achilles tendon thickness (ATT) on radiography was changed from ≥9 mm in both men and women to ≥8.0 mm in men and ≥7.5 mm in women. The current study aimed to validate the efficacy of this modification in independent samples. Methods: Patients with FH were retrospectively reviewed. The proportions of patients with pathogenic FH mutation who had an ATT of <7.5/8.0 mm (group 1), ≥7.5/8.0 and <9.0 mm (group 2), and ≥9 mm (group 3) were assessed. Results: In total, 492 patients were included in group 1, 102 in group 2, and 263 in group 3. Approximately 14.0%, 55.9%, and 79.8% of patients in groups 1, 2, and 3, respectively, exhibited FH mutation. Further, 37.3%, 77.3%, and 86.5% of patients with a low-density lipoprotein cholesterol level of ≥180 mg/dL in groups 1, 2, and 3, respectively, harbored FH mutation. Moreover, the median low-density lipoprotein cholesterol levels (157, 182, and 253 mg/dL, respectively) and the proportion of patients with protein-truncating mutation (3.8%, 16.7%, and 53.2%, respectively) had a significant trend. Conclusions: There was a substantial number of patients with FH who had an ATT of ≥7.5/8.0 and <9.0 mm. These patients previously had a deferred diagnosis of FH. However, they were diagnosed with FH based on the new clinical guideline.

Variants in LPA are associated with Familial Hypercholesterolaemia: whole genome sequencing analysis in the 100,000 Genomes Project.

Familial Hypercholesterolaemia (FH) is an inherited disease of high LDL-cholesterol (LDL-C) caused by defects in LDLR, APOB, APOE and PCSK9 genes. A pathogenic variant cannot be found in ∼60% of clinical FH patients. Using whole genome sequencing (WGS) we examined genetic determinants of FH. WGS data generated by the 100,000 Genomes Project (100KGP) included 536 FH patients diagnosed using the FH Simon Broome criteria. Rare variants in known FH genes were analysed. Genome-wide association study (GWAS) between 443 FH variant-negative unrelated FH cases and 77,275 control participants of the 100KGP was run using high coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (Lp(a) PRS) were computed. An FH-causing variant was found in 17.4% of FH cases. GWAS identified the LPA gene locus being significantly associated (p<1x10-8). FH variant-negative participants had higher LDL and Lp(a) PRSs in comparison to the controls (p<1.0×10-16 and p<4.09×10-6, respectively). Similar associations were found in the monogenic FH with both LDL and Lp(a) PRSs being higher than in controls (p<4.03×10-4 and p<3.01x10-3, respectively). High LDL PRS was observed in 36.4% of FH variant-negative cases, whereas high Lp(a) PRS in 18.5%, with 7.0% having both high LDL and Lp(a) PRSs. This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogenous architecture of hypercholesterolaemia, with the LPA gene playing a significant role. Both Lp(a) and LDL-C should be measured for precision FH diagnosis. Specific therapies to lower Lp(a) should be targeted to those who will benefit most.

LDL-C target attainment and statin use in patients with ASCVD, familial hypercholesterolaemia, and those otherwise at moderate/high-risk of ASCVD in australian general practice (SCOPE-GP)

Abstract Background The proportion of Australian general practice patients not attaining low-density lipoprotein cholesterol (LDL-C) goals is not well described. The SCOPE-GP study evaluated duration of LDL-C exceeding treatment goals, statin use and discontinuation rates in patients with atherosclerotic cardiovascular disease (ASCVD), without ASCVD events but at moderate/high-risk, and familial hypercholesterolemia (FH). Methods This population-based retrospective cohort study used de-identified medical records of adult patients captured in the IQVIA GP-EMR database. Patients were indexed at the earliest date of ASCVD, FH, or hyperlipidemia diagnosis from January 1, 2010 to June 30, 2022, with a variable follow-up period from index to June 30, 2022. Ascertainment of study cohort was based on the 2021 ESC/EAS guidelines and Framingham Risk Equation. LDL-C test result levels were extracted per patient, summarised and analysed. Patients were stratified based on their test results at latest results/closest to censor date. Average time above target levels is the proportion of number of days above LDL-C target levels over total number of follow-up days for each patient. A Poisson distribution was fitted to estimate 95% confidence interval. Lipid lowering therapies (LLT) were stratified by (ASCVD, FH and moderate/high risk of CVD) at last visit/censor date. Combination of LLT were defined as prescriptions for fixed dose combinations or ≥2 separate scripts of LLT from different classes within 180 days from last visit/censor date (look back period). Discontinuation is defined as no statins were prescribed again after the last script for 270 days or more, limited to the first occurrence. Results The average time with LDL-C levels above target was 1077.5 days in ASCVD patients (n=2,688), 938.6 days in moderate-risk ASCVD (n=37,003), 980.9 days in high-risk ASCVD (n=85,199), and 900.8 days in FH (n=279). The proportion of days above target level for all four cohorts is described in Figure 1. Among 107,552 patients with recorded LDL-C levels ≥1.8mmol/L at their last visit/censor date, 30.9% were on statin monotherapy and 1.0% were on statin+ezetimibe. Statin use was highest in ASCVD patients (65.4%), followed by FH (49.5%), high risk (40.0%) and moderate risk subjects (29.5%) (Table 1). Statin discontinuation rates were 60.3%, 76.3, 66.1%, and 65.8% in these groups, respectively. The predominant reason for statin discontinuation was non-specific adverse drug reactions (12.2% ASCVD, 11.7% moderate-risk, 13.2% high-risk and 17.9% FH). The proportion of subjects contraindicated to statins was highest in moderate risk subjects (0.05%). Conclusions Prolonged periods of elevated LDL-C and high statin discontinuation rates were prevalent among at-risk individuals in Australian primary care. This underscores a significant ASCVD burden that could be prevented with more active lipid management.

The effectiveness and barrier of reverse cascade screening for paediatric familial hypercholesterolaemia

Abstract Background Familial Hypercholesterolaemia (FH) is an autosomal dominant genetic disorder that is prevalent in one out of every 300 individuals in the general population. Recognized as an actionable condition, early diagnosis of FH in children is crucial to prevent the onset of atherosclerosis, and equally important is the identification of parents before the development of coronary artery disease events. Therefore, the significance of universal FH screening during childhood combined with reverse cascade screening has been increasingly acknowledged. To achieve these objectives, in our region, universal lipid screening is conducted in elementary schools for children aged 9 or 10 years, annually screening approximately 8,000 individuals, with those identified being referred through a three-step process to four major healthcare facilities within the prefecture. However, the effectiveness of reverse-cascade screening remains unclear. Purpose Our study aimed to assess the effectiveness of and identify barriers to implementing reverse cascade screening in conjunction with universal lipid screening. Methods We conducted a single-center, retrospective observational study from January 2018 to July 2023 and evaluated the utility of reverse cascade screening for children genetically diagnosed with FH following universal screening. This study analysed prevalent barriers and identified families with suspected FH through reverse cascade screening, counting those with Potential FH among second-degree relatives. Beyond successful identification, we categorized the frequently encountered barriers into five distinct categories: bereavement, prior cardiovascular events, dyslipidaemia with unspecified LDL-C levels, incomplete family history information, and inadequate disease awareness of FH. Reverse FH diagnosis adhered to current guidelines. Results and Discussion Of 151 paediatric patients referred to our facility, 67 were genotypically confirmed to have FH. Excluding 8 cases of divorce and 4 cases of tracking challenges, 55 patients were finally analysed. 62 patients were diagnosed with reverse FH, and appropriate treatment was initiated. Notably, 158 cases of Potential FH were identified. (25 first-degree and 133 second-degree relatives). While a higher number of reverse FH diagnoses were observed in first-degree relatives (55 cases), the diagnostic yield was lower among second-degree relatives (seven cases). Common barriers for second-degree relatives included dyslipidaemia with unspecified LDL-C levels (42 cases) and incomplete family history information (66 cases). Conclusion Integrating universal screening with reverse cascade screening facilitates the identification of new FH cases. A comprehensive strategy for diagnosing reverse FH is paramount, raising disease awareness, genetic testing, the development of a family-based care plan, and enhancing access to information and communication technologies.

Feasibility study to boost ascertainment of FH in diverse primary care populations using FAMCAT tool and pharmacist review

Abstract Background Familial Hypercholesterolaemia (FH) is a greatly underdiagnosed genetic lipid disorder with high risk of morbidity from premature cardiovascular disease. However, early diagnosis can significantly reduce cardiovascular risk with lipid-lowering medicines. Patients identified with high risk primary dyslipidaemia are recommended for lipid clinic referral to inform patient management. Improving FH identification and addressing ethnic disparities in dyslipidaemia management, is a current NHS priority in the UK. Aim We aimed to explore inequalities in the FH care pathway within and across areas with different socio-demographic UK populations. Methods The study was carried out in 6 general practices in the South East of England with divergent ethnic densities and socioeconomic status. Eligible patients aged 18 years or over, fulfilling the NICE (1), Simon-Broome (2) and current NHS Directed Enhanced Service criteria (3) for possible FH were screened using our previously validated PRIMIS FAMCAT2 tool (4) to prioritise those most likely to have FH. The PRIMIS FAMCAT2 tool generated a report highlighting patients with a "High Risk" of FH Tier 1 and a "Higher Risk if family history is positive" of FH- Tier 2. Tier 1 patients were assessed for FH using local lipid pathways. For the 243 Tier 2 patients, an online family history questionnaire/telephone enquiry was administered. The accuracy of the information collected was assessed by a practice-based clinical pharmacist (overseen by the GP). This included repeat testing for full lipid profile, excluding secondary causes of raised cholesterol. New patients meeting the criteria for FH were referred to a lipid/specialist clinic to assess for genetic testing. Patients who did not meet the FH criteria were managed accordingly to the local lipid pathways. Results 131,930 records from 6 general practices in South East England were screened using the PRIMIS FAMCAT tool. In total, the high priority list yielded 369 patients (126 Tier 1 and 243 Tier 2). Ethnicity breakdown was White (40%), Asian (8%), Black African/Caribbean (22%), Mixed (14%), Other (16%) NS (1%). A total of 25/369 (7%) patients were previously referred to lipid clinics (4 underwent genetic testing, 2 had confirmed FH, 12 did not have FH, and 7 were not seen/missed appointments). There were 14/244 (4%) new referrals to lipid clinics. Only 1 patient had received a coded FH diagnosis in the primary care record. For Tier 2 patients, 65/243 (27%) patients completed an online family history questionnaire, the remainder were ascertained by phone (75% response rate overall). Conclusion Incorporating enhanced case-finding from electronic medical records based on current guidelines, and online family history questionnaire can enhance FH identification. However large inequalities remain in referral, attendance and testing at lipid clinics, and further work is underway to evaluate the FH care pathway in diverse populations.

The effect of lipid-lowering treatment on indices of MASLD in familial hypercholesterolemia patients

Background & AimsThe effect of lipid-lowering treatment (LLT) on metabolic dysfunction associated steatotic liver disease (MASLD) is unclear. This is relevant for patients with familial hypercholesterolemia (FH) who are on lifelong LLT. We aimed to evaluate the effect of LLT on MASLD indices in this population. MethodsPatients with at least possible diagnosis of FH were included into the Hellenic FH Registry (HELLAS-FH) registry. We analyzed the effect of statin monotherapy, statin/ezetimibe and statin/ezetimibe/proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) on MASLD indices, i.e., original triglyceride-glucose index (TyGO) and triglyceride-glucose index (TyG). We compared changes of TyG and TyGO before any treatment and after at least one year of stable LLT. ResultsWe included 1289 patients: n=569 in the statin monotherapy group (mean age=51±15 years, 52.7% males), n=629 in the statin/ezetimibe group (52±14 years, 51.8%), and n=91 in the statin/ezetimibe/PCSK9i group (54±13 years, 58.2%). Compared with baseline, TyGO and TyG decreased significantly following statin monotherapy (8.61 vs 8.49 and 4.65 vs 4.59, respectively, both p<0.01), statin/ezetimibe (8.59 vs 8.41 and 4.64 vs 4.55, respectively, both p<0.01) and statin/ezetimibe/PCSK9i (8.79 vs 8.55 and 4.74 vs 4.62, respectively, both p<0.01). There was no difference regarding the change of TyGO and TyG between groups after adjusting for baseline levels. A greater percentage of patients in the statin/ezetimibe and statin/ezetimibe/PCSK9i groups exhibited TyGO-defined MASLD resolution compared with statin monotherapy (p<0.05). After adjustment for possible confounders, LLT was significantly associated with MASLD resolution. ConclusionsMASLD indices were significantly improved in all LLT groups in FH patients. Statin/ezetimibe and statin/ezetimibe/PCSK9i were associated with greater TyGO-defined MASLD resolution compared with statin monotherapy.

Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a monogenic hereditary disease with an estimated prevalence of 1:220-1:250 in Denmark; the majority have not yet been diagnosed. Untreated FH is associated with a considerably increased risk of premature cardiovascular disease. Early treatment significantly reduces risk, stressing the importance of early diagnosis and treatment initiation. General practicians have a key role in screening and referring patients. Diagnosis, cascade screening, and treatment of FH are handled by Lipids Clinics. For FH, this review finds that initiation of treatment is recommended from age 7-10.

Familial hypercholesterolaemia with high triglycerides: A diagnostic challenge.

Combined or mixed hyperlipidaemia is characterised by hypercholesterolaemia together with high triglyceride concentrations. It is found in approximately 1 in 100 people in the United Kingdom. Most cases are secondary to an underlying condition such as the metabolic syndrome, diabetes mellitus (especially poorly controlled) or individuals with a high alcohol intake. Mixed hyperlipidaemia is also a feature of some primary hyperlipidaemia conditions such familial combined hyperlipidaemia (FCH) or type III hyperlipidaemia (dysbetalipoproteinaemia). One differential diagnosis for mixed hyperlipidaemia that can easily be overlooked is a patient with an underlying diagnosis of familial hypercholesterolaemia (FH) who also has a hypertriglyceridaemia due to any other cause. Those patients may have very high total and low-density lipoprotein cholesterol concentrations (LDL-C) with a moderately elevated triglyceride concentration. In this article, we report 4 cases of familial hypercholesterolaemia, confirmed by genetic testing, in patients initially presenting with hypertriglyceridaemia in addition to high total cholesterol and LDL-C. This article discusses the diagnostic challenges associated with this presentation and highlights the key role of directly measuring LDL-C to aid diagnosis in these specific situations.

An 8-SNP LDL Cholesterol Polygenic Score: Associations with Cardiovascular Risk Traits, Familial Hypercholesterolemia Phenotype, and Premature Coronary Heart Disease in Central Romania.

Familial hypercholesterolemia (FH) is the most significant inherited risk factor for coronary heart disease (CHD). Current guidelines focus on monogenic FH, but the polygenic form is more common and less understood. This study aimed to assess the clinical utility of an 8-SNP LDLC polygenic score in a central Romanian cohort. The cohort included 97 healthy controls and 125 patients with premature (P)CHD. The weighted LDLC polygenic risk score (wPRS) was analyzed for associations with relevant phenotypic traits, PCHD risk, and clinical FH diagnosis. The wPRS positively correlated with LDLC and DLCN scores, and LDLC concentrations could be predicted by wPRS. A trend of increasing LDLC and DLCN scores with wPRS deciles was observed. A +1 SD increase in wPRS was associated with a 36% higher likelihood of having LDLC > 190 mg/dL and increases in LDLC (+0.20 SD), DLCN score (+0.16 SD), and BMI (+0.15 SD), as well as a decrease in HDLC (-0.14 SD). Although wPRS did not predict PCHD across the entire spectrum of values, individuals above the 90th percentile were three times more likely to have PCHD compared to those within the 10th or 20th percentiles. Additionally, wPRS > 45th percentile identified "definite" clinical FH (DLCN score > 8) with 100% sensitivity and 45% specificity. The LDLC polygenic score correlates with key phenotypic traits, and individuals with high scores are more likely to have PCHD. Implementing this genetic tool may enhance risk prediction and patient stratification. These findings, the first of their kind in Romania, are consistent with the existing literature.

The therapeutic effect of PCSK9 inhibitors on dyslipidemia: one-year follow up.

Despite the availability of statins and lifestyle modifications, many patients with Dyslipidemia struggle to achieve optimal low-density lipoprotein cholesterol (LDL-C) control. PCSK9 inhibitors offer a promising new therapeutic option with superior LDL-C lowering efficacy compared to statins. However, data on their real-world use, particularly in Iran, is limited. This study aims to address this gap by investigating the one-year effects of evolocumab on lipid profiles and potential cardiovascular outcomes in Iranian patients with Familial Hypercholesterolemia (FH).This single-center, prospective study evaluated evolocumab effectiveness in lowering LDL-C in 50 Iranian adults with FH. Participants with a documented LDL-C > 190 mg/dL on existing cholesterol medications (excluding PCSK9 inhibitors) and a clinical FH diagnosis was included. After baseline assessments (medical history, demographics, lipid profile), evolocumab was administered subcutaneously every two weeks for one year. Follow-up assessments at year one measured changes in LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. The study enrolled 50 participants with an average age of 55 years old (range 35-80 years).Treatment with evolocumab led to significant improvements in lipid profiles at all follow-up points compared to baseline. On average, LDL-C levels decreased by 105.24 mg/dL, triglycerides decreased by 59.20 mg/dL, and HDL-C levels increased by a modest but significant 4.5 mg/dL after one year(p<0.001). Subgroup analysis revealed no statistically significant interactions between baseline demographics (age, sex, BMI) or lifestyle habits (smoking, alcohol) and changes in lipid levels(p>0.05). However, a significant interaction emerged between baseline lipid levels and their corresponding reductions, suggesting greater improvement in patients with higher baseline values(p<0.05). It is noteworthy that no new cardiovascular events were reported during the study period. This study demonstrates the effectiveness of evolocumab in improving lipid profiles in Iranian patients with FH. The observed reductions in LDL-C and triglycerides, along with a modest increase in HDL-C, suggest potential benefits for cardiovascular risk reduction. The absence of new cardiovascular events during the study is encouraging, but further research with larger and longer-term follow-up is needed to confirm these findings and assess the long-term safety and impact on quality of life.

Familial Hypercholesterolaemia Patients with LDLR Mutation Among Asian Population in Southeast Asian Countries: Systematic Review

Familial hypercholesterolaemia (FH) is a genetic disorder associated with premature cardiovascular diseases; however, the majority of patients remain undertreated. This systematic review aimed to determine the prevalence of FH patients with low-density lipoprotein receptor (LDLR) gene pathogenic variants (PV) among the Asian population in Southeast Asian countries. Our search yielded 1,120 citations, with 28 deemed possibly suitable based on title and abstract screening. However, only six studies that utilised the Dutch Lipid Clinic Network (DLCN) or Simon Broome (SB) criteria were eligible to be included. These studies provided prevalence figures for clinically diagnosed FH patients, with a total of 17.1% (n=1,005/5,874); this rate was represented by three Malaysian studies, which estimated that 36–76% of clinically diagnosed FH patients had LDLR PV. Most patients reported having pre-existing cardiovascular disease, a family history of premature coronary artery disease and tendon xanthomata. This study found that the prevalence of LDLR PV among genetically confirmed FH patients in Southeast Asia is 20.5% (n=286/5,874). Genetically confirmed FH patients are at a higher risk of developing premature coronary artery disease, requiring more aggressive lipid-lowering treatment. Therefore, identifying LDLR PV among the population is essential for early FH diagnosis and treatment. KEYWORDS Arterial disease, autosomal dominant, LDL receptor, LDLR prevalence, pathogenic variants, premature CAD, Undertreated

The Prevalence of Different Genotypic Forms of Familial Hypercholesterolemia in Relation to Race and Ethnicity

In the present study, a systematic literature review was conducted to examine the prevalence of homo- and heterozygous forms of Familial hypercholesterolemia among different racial and ethnic groups. Familial hypercholesterolemia (FH) is an inherited disorder characterised by elevated blood levels of cholesterol and low-density lipoprotein (LDL), which increases the risk of cardiovascular disease. Databases PubMed, Web of Science, and Elsiever were searched and only peer-reviewed articles with a large number of contributors and sufficient prevalence and ethnicity data were included. Diagnosis of FH was based on genetic testing or clinical criteria. The results of the study indicate inadequate and untimely diagnosis of FH, resulting in inadequate treatment. To date, only 9% of countries have statistical data on the prevalence of FH in the general population. In order to develop effective prevention strategies for cardiovascular diseases associated with FH, further research is needed to obtain accurate epidemiological data, including the race and ethnicity of patients. This will allow optimisation of strategies to reduce the burden of preventable cardiovascular disease associated with FH.&lt;br /&gt; &amp;nbsp;

"I don't think people should die young": perspectives of parents with children diagnosed with familial hypercholesterolemia.

Familial Hypercholesterolemia (FH) is an inherited disorder that significantly increases an individual's risk of developing premature cardiovascular disease (CVD). Early intervention involving lifestyle modification and medication is crucial in preventing CVD. Prior studies have shown that lipid-lowering therapy in children is safe and effective. Despite FH being a treatable and manageable condition, the condition is still underdiagnosed and undertreated. Universal lipid screening (ULS) in children has been recommended by some medical experts in the United States as a strategy to identify cases of FH and maximize the benefits of early invention. However, lipid screening is not routinely offered in pediatric clinics. This study aimed to explore parental experience with FH diagnosis in their children, identify key facilitators and barriers in children's diagnosis and care, and examine parental perspectives on ULS in children in the United States. A total of fourteen semi-structured interviews were conducted with participants recruited through the Family Heart Foundation. Thematic analysis identified three key themes: role of family history in facilitating child's FH diagnosis, barriers and challenges in post-diagnosis care, and attitudes towards ULS in children. All participants supported ULS in children and emphasized the value of early diagnosis and treatment for FH. However, a lack of guidance or referral after the child's diagnosis was a concern raised by many participants. This underscores the need for accessible and comprehensive care amid ongoing efforts to increase pediatric diagnosis of FH.

Prompt Cytopathological Diagnosis of Multiple Xanthomatous Skin Nodules in an Adolescent Girl Opening the Doors to Detection of Familial Hypercholesterolemia

Background Xanthomas are papulo-nodular, yellow, soft, painless, dermal-based non-neoplastic cutaneous lesions that comprise of localized aggregates of lipid-laden histiocytes. Case report A thirteen-year-old adolescent girl presented with multiple, large, bilateral, nodules present over elbows, posterior aspect of heel, and knees for five years. Fine needle aspiration cytology was performed, and the smears showed numerous foamy histiocytes, a few benign spindle cells, and foreign-body giant cells against a lipidaceous background. Her maternal aunt and grandmother also had xanthelasma palpebrarum. Serum lipid levels were advised and were markedly deranged in all three of them. Based on the corroborative clinical, biochemical, and cytopathological findings, a final diagnosis of familial hypercholesterolemia (FH) was rendered. Conclusion The present case sheds light on the importance of prompt cytopathological diagnosis of xanthomatous lesions, especially in children and adolescents, as it can help prevent morbidity and mortality due to associated premature adverse cardiovascular and cerebrovascular events if left undiagnosed.

Familiar Hypercholesterolemia, Overview: A Lethal Hereditary Disorder with Simple Diagnosis and Affordable Treatment.

Familial hypercholesterolemia (FH) is an underdiagnosed disorder characterized by high concentration of low- density lipoprotein (c-LDL) from birth, and if left untreated, causes premature cardiovascular morbidity and mortality. An effective and inexpensive method for detecting FH is to determine c-LDL, and genetic study reveals asymptomatic relatives. The most frequent mutations occur in the LDL receptor gene (RLDL) and the least frequent are in apolipoprotein B100 (ApoB 100), apoprotein convertase subtilisin/kexin 9 (PCSK9) and LDL receptor adaptor 1 (RLDLAP1). Patients with heterozygous FH (HFHe) have c-LDL levels above 190 mg/dL; homozygous patients (HFHo) have the most severe form, with c-LDL above 500 mg/dL. Treatment is a low-fat diet and lipid-lowering drugs, mainly statins in combination with cholesterol absorption inhibitors (ezetimibe). In HFHo or severe heterozygotes resistant to treatment, the use of anti-PCSK9 monoclonal antibodies and c-LDL apheresis is considered, however, this is not available in countries such as Mexico. Even the lack of governmental programs for the systematic detection of FH is frequent. Therefore, this panoramic review shows the generalities, genetic basis, diagnosis, clinical characteristics, and treatment of FH, with the purpose of informing and calling the attention of health professionals, legislators, and the population at large.

Efficacy of Alirocumab, Evolocumab, and Inclisiran in Patients with Hypercholesterolemia at Increased Cardiovascular Risk.

Background and Objectives: Lowering low-density lipoprotein (LDL-C) levels is critical for preventing atherosclerotic cardiovascular disease, yet some patients fail to reach the LDL-C targets despite available intensive lipid-lowering therapies. This study assessed the effectiveness and safety profile of alirocumab, evolocumab, and inclisiran in lipid reduction. Materials and Methods: A cohort of 51 patients (median (Q1-Q3) age: 49.0 (39.5-57.5) years) was analyzed. Eligibility included an LDL-C level > 2.5 mmol/L while on the maximum tolerated dose of statin and ezetimibe, a diagnosis of familial hypercholesterolemia, or a very high risk of cardiovascular diseases following myocardial infarction within 12 months prior to the study. Follow-ups and lab assessments were conducted at baseline (51 patients), 3 months (51 patients), and 15 months (26 patients) after the treatment initiation. Results: Median initial LDL-C levels 4.1 (2.9-5.0) mmol/L, decreasing significantly to 1.1 (0.9-1.6) mmol/L at 3 months and 1.0 (0.7-1.8) mmol/L at 15 months (p < 0.001). Total cholesterol also reduced significantly compared to baseline at both intervals (p < 0.001). No substantial differences in LDL-C or total cholesterol levels were observed between 3- and 15-month observations (p > 0.05). No statistically significant differences were noted in cholesterol reduction among the alirocumab, evolocumab, and inclisiran groups at 3 months. The safety profile was favorable, with no reported adverse cardiovascular events or significant changes in alanine transaminase, creatinine, or creatine kinase levels. Conclusions: Alirocumab, evolocumab, and inclisiran notably decreased LDL-C and total cholesterol levels without significant adverse effects, underscoring their potential as effective treatments in patients who do not achieve lipid targets with conventional therapies.

Potentials of artificial intelligence in familial hypercholesterolemia: Advances in screening, diagnosis, and risk stratification for early intervention and treatment

Familial hypercholesterolemia (FH) poses a global health challenge due to high incidence rates and underdiagnosis, leading to increased risks of early-onset atherosclerosis and cardiovascular diseases. Early detection and treatment of FH is critical in reducing the risk of cardiovascular events and improving the long-term outcomes and quality of life for affected individuals and their families. Traditional therapeutic approaches revolve around lipid-lowering interventions, yet challenges persist, particularly in accurate and timely diagnosis. The current diagnostic landscape heavily relies on genetic testing of specific LDL-C metabolism genes, often limited to specialized centers. This constraint has led to the adoption of alternative clinical scores for FH diagnosis. However, the rapid advancements in artificial intelligence (AI) and machine learning (ML) present promising solutions to these diagnostic challenges. This review explores the intricacies of FH, highlighting the challenges that are encountered in the diagnosis and management of the disorder. The revolutionary potential of ML, particularly in large-scale population screening, is highlighted. Applications of ML in FH screening, diagnosis, and risk stratification are discussed, showcasing its ability to outperform traditional criteria. However, challenges and ethical considerations, including algorithmic stability, data quality, privacy, and consent issues, are crucial areas that require attention. The review concludes by emphasizing the significant promise of AI and ML in FH management while underscoring the need for ethical and practical vigilance to ensure responsible and effective integration into healthcare practices.

Familial Hypercholesterolemia Diagnosis and Management: Insights from the NIH Precision Medicine Initiative All of Us Study

Familial Hypercholesterolemia Diagnosis and Management: Insights from the NIH Precision Medicine Initiative All of Us Study